Access to taxol analogs

ABSTRACT

Transformations of taxol, baccatin III and of 10-deacetyl baccatin III provide access to novel taxol analogs and key intermediates thereto.

This is a divisional of application Ser. No. 08/110,095, filed Aug. 20,1993 whose disclosures are incorporated herein by reference now U.S.Pat. No. 5,440,057.

FIELD OF INVENTION

The invention relates to taxol and to the synthesis of taxol analogs.More particularly, the invention relates to processes and keyintermediates for synthesizing taxol analogs.

BACKGROUND

Taxol is a natural product with anti-cancer activity. Because naturalsources of taxol are limited, synthetic methods for producing taxol havebeen developed, e.g., K. C. Nicolaou et al., J. Chem. Soc., Chem.Commun. 1992, 1117-1118, J. Chem. Soc., Chem. Commun. 1992, 1118-1120,and J. Chem. Soc., Chem. Commun. 1993, 1024-1026. Several synthetictaxol analogs have also been developed and have been found to havealtered chemical and biological activity as compared to natural taxol,e.g., K. C. Nicolaou et al., Nature, 1993, 364, 464-466. There isconsiderable interest in the design and production of further taxolanalogs. However, progress with respect to the synthesis of such taxolanalogs has been blocked by a lack of information regarding certain keysynthetic methods and key intermediates essential for the production ofa wide range of taxol analogs.

What is needed is the identification of key synthetic methods and keyintermediates for producing taxol analogs having altered activities.

SUMMARY

Novel transformations of taxol, baccatin III and of 10-deacetyl baccatinIII are disclosed. These transformations and key intermediates provideaccess to novel taxol analogs.

DETAILED DESCRIPTION

We disclose herein degradative studies of the natural taxol product. Ourobjectives are bipartite: we provide first hand knowledge about thechemistry of those compounds arising late in our synthetic plan (supra)and we also provide access to the synthesis of derivatives which havenot been previously explored. ##STR1##

Our initial goal was to produce a C1-C2 vicinal diol that could be usedto explore benzylation of the C2 hydroxyl group, a process that weconsidered crucial to the success of our synthetic endeavors. Towardsthis end, reductive deesterification of taxol (1) followed by selectivesilylation of the C7 hydroxyl group with triethyl silyl chloride(TES-Cl) produced, as per literature precedent (Nicolaou, supra; N. F.Magri et al., Journal of Organic Chemistry 1986: vol. 51, pages3239-3242; and J. -N. Denis et al., Journal of the American ChemicalSociety 1988vol. 110, pages 5917-5919), 7-TES Baccatin III (2) (Scheme1). All attempts to selectively deprotect the C2 and C10 positions,including both metal hydride reduction and basic hydrolysis, produced amixture containing completely deesterified materials and rearrangedproducts giving extremely low (15-30%) yields of the desired compound 4,a result which is in accordance with other groups result's. Wehypothesized that oxidation of the C13 hydroxyl group would remove asuspected hydrogen bond between this hydroxyl group and the C4 acetoxygroup thus rendering the acetyl group less susceptible to bothnucleophillic deprotection processes. Indeed, catalytic oxidation withLey's ruthenium system gave the C13 ketone that was readily hydrolyzedunder basic conditions to provide a single product, 4, in high yield.Subsequently, we found that this material could be easily produced fromall three of the commonly available taxoid natural products: taxol,baccatin III, and 10-deacetylbaccatin III. This enone triol 4 gave aconvenient starting point for all of our further studies.

During our preliminary survey of methods for selectively introducing theC2 benzoyl group, we envisaged the possibility of directly converting aC1-C2 carbonate into a C2 benzoate by the simple addition of anucleophillic phenyl reagent. This method would provide a double role tothe carbonate: first as a convenient protecting group during a totalsynthesis of taxol and later as a direct provider of the crucialbenzoate. As shown in Scheme 2, this method was readily reduced topractice. Treatment of 4 with phosgene in freshly distilled pyridineprovided the desired carbonate, 5, in good yield. Simple addition of anexcess of phenyllithium to a THF solution of this carbonate at -78° C.gave the benzoate as the single product. Acylation under standardconditions gave the enone 7. We have shown that protection of the C10hydroxyl group is unnecessary and that if the C10 acetyl compound issubjected to this protocol partial deacylation of the 10-positionoccurs. This result leads us to expect easy access to a variety of C2esters, a class of derivatives which was previously inaccessible and mayprove very important given that moietie's importance in taxols SAR. Aseries of these proposed derivatives is also given in Scheme 2. ##STR2##

Another important step in our total synthesis of taxol is theintroduction of the oxygenation at the C13 position. As shown in Scheme3, we employed a two step radical deoxygenation of 2 to give the C13deoxy compound 8 as an inseparable mixture of tri- and tetra-substituted alkenes. Deprotection/reprotection according to our protocoldescribed above is expected to give rise to the carbonate 9. Thismaterial should be readily converted to 6 by chromium mediated allylicoxidation. ##STR3##

Conversion of 7 back to taxol proceeded according to literatureprecedent. Acylation at the C10 position smoothly gave the expectedenone acetate. Treatment of this material with sodium borohydride gave,with exclusive regio and stereo chemistry, the correct C13 alcohol.Introduction of the protected side chain, followed by deprotectionshould give taxol 1. ##STR4##

Since our synthetic strategy for taxol centers around the reductivecoupling of a dialdehyde to produce the C9-C10 bond, we undertookstudies aimed at oxidatively cleaving this bond. Initial attempts withlead tetraacetate on both taxol (1) and 10-deacetyl baccatin III (3)failed to produce cleavage products. As shown in Scheme 5, the majorproduct in the case of 3 was that of oxidation at the C13 position.Similar studies on the enone 6, failed, with a variety of reagents, toproduce any cleavage products. ##STR5##

Since our synthetic intermediates were not protected in exactly the samemanner as our degradation products, we attempted to protect both theC1-C2 diol and the C7 hydroxyl group with a variety of moieties. Asshown in Scheme 6, all attempts to introduce acetal or ketal groups atC1-C2 gave exclusive rearrangement to the cyclic ether 12. A similarether has been proposed as the major side product during attempts todeprotect Baccatin III. As shown in Scheme 7, attempts to introduceother ethereal protecting groups than the TES resulted in either noreaction, exclusive epimerization at the C7 position, or opening of theoxetane via elimination. ##STR6##

What is claimed is:
 1. An improved method for producing key intermediate4starting from a taxoid natural product, the improvement comprising thefollowing steps: Step A: providing the taxoid natural product; then StepB: catalytically oxidating the taxoid natural product using Ley'sruthenium system to give a C13 ketone; and then Step C: hydrolyzing theproduct of said Step B under basic conditions to provide keyintermediate
 4. 2. A taxol analog having a C2 ester having the followingstructure: ##STR7## wherein G is selected from the group consisting of:##STR8## wherein: R is a radical selected from the group consisting ofalkyl, alkoxy, nitro, and halogen;X is a radical selected from the groupconsisting of CH, and N; and Y is a radical selected from the groupconsisting of CH, N, S, and O.